Project abstract Prion diseases are fatal neurodegenerative diseases caused by conversion of the cellular prion protein, PrPC, into a self-propagating misfolded form called the scrapie prion protein, or PrPSc. Previous efforts to develop small molecule drugs against prions have screened compounds in prion-infected mouse cells, and have led to the discovery of molecules that are effective at extending life in prion-infected mice, but not in mice expressing human PrP and infected with human prions. This project aims to lay the groundwork for drug discovery efforts aimed specifically at human PrP and human prions. The specific aims are to 1) identify PrP-binding compounds, 2) identify low molecular weight fragments that stabilize PrP, and 3) characterize the kinetics of human prion uptake and clearance in cultured cells, a first step towards developing human prion infected cell lines for drug screening.